Monday October 10, 2022
Retinoblastoma care is a complex balancing act. Some children receive too little treatment, while others receive more than necessary, with potentially devastating results. Sharing two children’s stories, Rb survivor Abby White explores what under- and over-treatment are, when they may happen, their consequences, and how we can prevent them.
When a child has retinoblastoma, there may be a fine line between the right amount of treatment and effort to save eyes and sight, too much treatment of a dangerous eye, and not enough treatment to protect the child’s life. Two mothers share their children’s stories…
Emma was diagnosed with unilateral right eye Group D retinoblastoma when she was 13 months old. She had one large tumor with extensive seeds.
IAC was recommended, with the goal of saving Emma’s vision. The risks concerned us (toxic drugs, bleeding and blood clots, loss of vision, even stroke), but we trusted the ophthalmologist, one of the world’s most experienced retinoblastoma specialists. They assured us Emma’s life would never be in danger, and IAC offered the best outcome – saving her eye with useful vision. Of course we wanted that for Emma, so she began IAC one week after diagnosis.
After three rounds of IAC, we were told the seeds were gone and the main tumour was mostly dead. Laser and cryo continued, but five months later, a “snowstorm” of new seeds prompted three more rounds of IAC that ended just after her 2nd birthday.
There was nearly always something to treat at each EUA. Six months after the first relapse, the main tumor regrew, and the doctor recommended a seventh round of IAC. We asked again about enucleation; the doctors again assured us that Emma’s life was not at risk, and again we trusted their expertise.
After that treatment, Emma lost the sight she’d gradually recovered. At the next EUA, the doctor said her eye was stable, with no damage to the ophthalmic artery or optic nerve, and the vision would likely return.
3 months later, Emma’s Iris began to change color, like we were seeing it through a fine mist. An emergency EUA found her iris was full of seeds. Her eye was enucleated two days later.
Pathology reported invasion of the choroid and ciliary body, but the ophthalmologist insisted chemotherapy wasn’t needed as there was minimal risk of spread. We sought a second opinion, and were advised to urgently begin chemotherapy. Waiting for the pathology consult and second opinion, then changing hospitals caused a five week delay in treatment.
Emma had six cycles of systemic chemotherapy. Six months after the last cycle, our worst fears were realised when she began to feel constantly tired; the cancer was in her bone marrow.
She endured four gruelling rounds of high-dose chemo, followed by a stem cell transplant. That involved a week of super-intensive chemotherapy to destroy her bone marrow, and months of recovery in isolation.
Five years later, Emma is cancer-free. But she had totally preventable life-threatening metastasis, and so much unnecessary toxic treatment and trauma that has weakened her body and changed her personality.
My husband and I wanted to save Emma’s eye, but her life is much more precious. Time and again, the ophthalmologist convinced us enucleation wasn’t necessary. I wish I had understood we were holding our princess far over the cliff. Enucleation was a necessary sacrifice to save her life. Why were we talked out of it?
On May 25, 2014, while getting ready for an outing to the beach, I noticed Damian’s pupil was fixed and dilated. A trip to the ER that day revealed advanced retinoblastoma in his left eye. Damian was two-years-old.
Treatment began with the goal of saving his eye. Enucleation was not proposed at diagnosis or during eye-salvage therapy. However, after 7 cycles of IAC and countless lasers, the cancer continued to resist treatment. Damian’s eye was eventually removed on July 2, 2015 – one year, one month, and one week after diagnosis.
Pathology and MRI reports both indicated high risk of cancer spread beyond Damian’s eye, but chemotherapy was delayed by almost 9 weeks while his doctors debated the situation. On September 8, 2015, we were devastated to be told the cancer had metastasized to his brain.
Damian began a year of aggressive treatment, including 6 cycles of high dose systemic chemotherapy, 30 sessions of craniospinal proton radiation, and stem cell transplant, but the cancer relapsed in his brain and spine.
On September 7 2016, Damian had No Evidence of Disease. Within 20 days, the cancer engulfed his brain and spinal fluid, and he was moved to hospice care. He began one final course of treatment – intrathecal chemotherapy (ITC) directly into his cerebrospinal fluid, along with more systemic chemotherapy.
The day after the first dose of ITC, he lost all vision in his remaining eye due to the cancer’s full invasion of both optic nerves. After four rounds of ITC, the cancer continued to progress, and all treatment stopped on October 21.
Damian died two weeks later, on November 5, 2016. At 4.5 years old, he lost his life to unilateral, non-heritable retinoblastoma.
Before and during eye salvage therapy, I asked many times about the stage of my son’s cancer. The ocular oncologist told me retinoblastoma is hard to grade for many reasons. I didn’t learn until after Damian died that his eye was graded Group E – the most advanced stage of intraocular retinoblastoma.
Damian’s father and I were unaware of the risk posed to his life by eye-saving treatment. Like most parents, we had no prior knowledge of retinoblastoma.
We trusted our son’s expert physician to guide us in making the best decisions. Damian was curable at diagnosis. So why did he die two and a half years later?
Forever four years old; Damian was an impish superhero with a captivating sunshine smile. Lover of hugs and kisses, first responders, fire trucks, Spiderman and all things superhero.
New tumour growth and relapse within the eye are common among children who have eye salvage treatment. More tumours may form, and old tumours may re-grow. Most children experience multiple, frequent relapses or new tumours over several years, and ocular oncologists familiar with retinoblastoma expect this.
The risk of further cancer activity within the eye depends on genetics and the type of retinoblastoma, stage of disease at diagnosis, and treatment history. Together, these factors guide appropriate follow up care when each course of treatment ends.
Life-threatening relapse outside the eye may occur when the child has advanced intraocular retinoblastoma. This risk is the same for children with unilateral and bilateral cancer. Relapse is more likely when treatment and follow-up are inconsistent and incomplete, or inappropriate for the stage of intraocular cancer.
Under-treatment and over-treatment can occur when the child’s therapy and/or follow-up care does not match their stage of cancer.
The terms under-treatment and over-treatment are not clearly defined in childhood cancer care. However, generally within medical care, they mean the following:
Under-Treatment: Insufficient, or less than recommended therapy and surveillance for the stage of a medical condition, increasing the risk of sub-optimal outcomes.
Over-Treatment: intensive therapy and surveillance in which the potential side-effects and risks outweigh the potential benefits.
A child with retinoblastoma may experience both under-treatment of life-threatening cancer, and over-treatment of cancer within the eye. Imagine a child who receives eye-salvage therapy for unilateral advanced intraocular retinoblastoma that has already destroyed sight.
- Therapy may fail to treat cancer cells on the eye’s outer layers, increasing the risk of relapse outside the eye (under-treatment of the whole child).
- Physical and psychological effects of invasive eye-salvage therapy, and risk to the child’s life, may be greater than potential to save the eye with useful vision (over-treatment of the eye).
Cancer is staged to predict how effective different treatments are to save the person’s life. In retinoblastoma, each eye is staged independently to indicate likelihood that a treatment can safely save the child’s eye, and achieve useful vision. Cancer stage for a bilaterally affected child is based on the worst affected eye, as an indicator of risk to the child’s life.
“Intraocular retinoblastoma” means the clinical exam and imaging results suggest cancer is contained in the eye.
“Extraocular retinoblastoma” means the results indicate cancer has escaped the eye – this is of course a more advanced situation.
Two systems are commonly used today to stage retinoblastoma:
- The International Intraocular Retinoblastoma Classification (IIRC Groups A to E).
- The TNMH (Tumour, Node, Metastasis, and Heritability).
TNMH stages cT1a to cT3 are broadly similar to IIRC A-E, with some distinct differences. WE C Hope provides a detailed explanation of both staging systems.
Advanced intraocular retinoblastoma refers to TNMH cT2b and cT3, and IIRC Groups D and E.
Parents, please make sure you know your child’s individual staging at diagnosis and each stage of treatment, and understand what it means. Doctors, please give this information whether or not a parent asks for it. Staging provides vital context to enable informed decision making and parent consent throughout the child’s care.
A visual progression of retinoblastoma through the TNMH Staging System.
Who is At Risk for Under-Treatment or Over-Treatment?
Every child with retinoblastoma faces a risk of under-treatment and/or over-treatment, but some factors significantly increase risk.
- Children receiving eye-salvage therapy for advanced intraocular retinoblastoma. Particularly eye-focused therapies such as intra-arterial chemotherapy and intra-vitreal chemotherapy, which do not reach cancer cells on the eye’s outer layers or beyond.
- Children who receive inconsistent or incomplete therapy and / or follow-up eye exams after therapy (whether eye salvage or enucleation). This is particularly common among families who move frequently, in developing countries, and international patients, when access specialist care is difficult.
- Children diagnosed with unilateral retinoblastoma who receive inadequate surveillance of the cancer-free eye, when they are known to have an RB1 mutation, or their genetic status and risk to the eye are unknown.
- Children after enucleation when eye pathology fails to identify and report high risk features. Often this may be due to the ‘masking’ effects of initial chemotherapy shrinking tumour within the eye, suggesting a falsely low risk of cancer beyond the eye, and ‘downgrading’ the pathology.
- Children after enucleation when post-surgery care fails to quickly address high-risk pathology.
- Infants treated with low-dose chemotherapy that may cause the cancer to become chemo-resistant.
- Children receiving eye-salvage therapy for severely advanced intraocular retinoblastoma (eye staged IIRC Group E or TNMH cT3).
- Children receiving eye-salvage therapy when there is remote chance of saving or recovering sight, particularly when the child has unilateral retinoblastoma and the other eye has good vision.
- Children who receive chemotherapy after enucleation because eye pathology is unavailable, delayed or incomplete. This is common in developing countries, where accurate, timely ocular pathology is often limited or absent.
- Children who receive chemotherapy after enucleation because the pathology report cannot be trusted due to the potential “masking” effects of pre-surgery therapy.
- Children with unilateral retinoblastoma who continue to have surveillance Exams Under Anaesthesia for their cancer-free eye, after genetic testing has established there is no or remote risk to that eye (MYCN mutation is identified, or the tumour’s RB1 mutation is not found in blood). This also applies to siblings of a diagnosed child, when genetic testing eliminates their risk.
What Are the Consequences of Under-Treatment and Over-Treatment?
For both the child and their family, there are many consequences of too little, or too much treatment. Below are the most critical considerations for each scenario.
- Unseen cancer cells continue to multiply, and may spread outside the eye.
- Eye-salvage therapy may appear to kill retinoblastoma within the eye, while failing to treat cancer threatening the child’s life.
- The child ultimately requires significantly more intensive and prolonged therapy than could have been achieved with appropriate medical care. This therapy is more expensive, with far higher costs to the physical and psychological wellbeing of both child and family.
- The potential to cure decreases significantly when retinoblastoma escapes the eye. Even with the most advanced therapies, the child may die.
- The child may experience many more invasive medical procedures, therapies, and hospitalizations than necessary.
- Long-term physical and psychological impacts of retinoblastoma may be increased with prolonged therapy, including increased risk of second primary cancers and non-cancer health issues.
- Practical, relational, psychological, and financial cost to the entire family are higher than necessary.
- Family members and medical professionals may be less able to acknowledge the need for enucleation after even one round of eye-salvage therapy, potentially delaying life-saving surgery.
- When a blind eye is saved, or enucleation is delayed by prolonged eye-salvage therapy, cosmetic appearance and prosthesis fit are often poorer than can be achieved with immediate enucleation.
How Can Risk of Under-Treatment and Over-Treatment Be Reduced?
Appropriate medical care can be achieved through honest conversation, family support, solid research, and global collaboration.
All children receiving eye-salvage therapy or treatment for extraocular cancer should receive care at a specialist retinoblastoma program. Parents, do your research and ask questions to ensure your child’s doctors have appropriate knowledge and experience, and an effective multidisciplinary team.
Honest conversation between doctors and parents is vital when a child has advanced intraocular retinoblastoma. Particularly when discussing potential to save the eye and preserve or restore sight, risk to the child’s life, and benefits and risks of eye-salvage therapy vs enucleation. Honest conversation guides informed consent.
These conversations are also vital among ocular and paediatric oncologists, pathologists, specialist nurses, other professionals, parents and survivors in forums where treatments and patient care are discussed.
When a child has advanced intraocular retinoblastoma, primary enucleation does not always prevent metastatic spread. Multiple centres have documented cases in which children treated with primary enucleation still developed metastasis. However prompt primary enucleation dramatically reduces the risk of relapse and metastasis beyond the eye, and for most children, timely enucleation alone is curative.
We must urgently examine our individual and collective motivations for eye salvage therapy, and better understand how we can make optimal care decisions to protect the whole child.
Eye salvage therapy involves potentially years of relapse and more treatment, and at least three years of invasive procedures beyond the last active tumour that can be traumatic to the child. Research shows that children with unilateral or bilateral IIRC Group D cancer had three times as many EUAs with eye-salvage therapy, compared with primary enucleation.
Thinking carefully about the potential impacts and ultimate goals of treatment will help everyone make the best recommendations and decisions for the whole child and entire family. Rather than being driven by fear, ego, competition, or someone else’s goals.
The medical and support team should help families tap into any practical and psychosocial support programs, particularly those provided through the hospital’s paediatric oncology and child life programs, and programs tailored to retinoblastoma families. These programs can:
- Support and guide families through decision making.
- Provide practical, financial, and emotional support that helps reduce stress – which is vital for balanced decision-making.
- Connect parents and children with others affected by retinoblastoma.
- Encourage families facing difficult treatments and their impacts.
Family pr ograms are vital in resource-limited settings, often supporting access to care, and reducing the risk of abandoning therapy or follow-up. Abandonment of therapy and follow-up is the top cause of treatment failure among curable children in developing countries.
Knowledge and Understanding
Understanding retinoblastoma is vital for parents making treatment decisions, and for the professionals who advise parents and provide care. Here are five key things for parents and professionals to know:
- The child’s cancer staging, and what it means.
- Benefits, side effects and risks of each treatment option, including risk of relapse, both within and outside the eye.
- Frequency of eye exams after eye salvage therapy, compared with after enucleation.
- Need for surveillance exams of the unaffected eye, and for siblings, if the child has unilateral retinoblastoma.
- Retinoblastoma genetics and what they mean for the child’s care.
A breakout session at One Rb World 2017.
Research and Global Collaboration
Medical care should be guided by the evidence gained through research. This evidence also supports national and international agreements about the best ways to manage different aspects of retinoblastoma care. Rigorous clinical research and ethnographic study of the lived experience is needed to provide clear and reliable evidence for the best patient and family care.
Parents are the child’s best advocate, and informed advocates are empowered to make the best decisions. Invest time in understanding how retinoblastoma research works, and read widely around a particular topic. Be aware of cognitive bias (when we look only for information that supports what we believe or want to know), and be open to learning about all aspects of the topic, including those you fear.
We encourage all members of the retinoblastoma community – parents, survivors, professionals, and scientists – to get involved with patient-led initiatives that encourage quality research focused on real-world needs, and studies designed for inclusion of our diverse community. Advocate for more rigorous multicentre research and international collaboration to establish clear management guidelines. Guidelines can help with subjects like:
- Appropriate perinatal care for Infants at risk for or diagnosed with eye cancer.
- Appropriate management of high risk advanced intraocular retinoblastoma.
- Definition of high-risk pathology features, and appropriate post-surgery care.
- Lifelong care and cancer screening for people with RB1
Support organizations that develop, equip and empower specialist retinoblastoma programs around the world, particularly in developing countries. These national and international collaborations can:
- Build up all aspects of retinoblastoma care, including diagnosis and referral, treatment and follow-up, imaging and pathology, and psychosocial support.
- Increase early access to appropriate expert care, and reduce family burdens that currently lead to abandonment of therapy, treatment failure, and preventable death.
- Save more children’s lives and sometimes sight – where safe to do so.
Retinoblastoma care is complex for many families and treatment teams. Under-treatment and over-treatment are very real risks, and increasing reality, with potentially devastating results. Medical professionals, families, and survivors must be aware of these risks, especially in the increasing push to save all eyes with retinoblastoma. We must all work together to ensure each child and family receives appropriate care, and the best chance of a long, happy and healthy life beyond their eye cancer diagnosis.
About the Author
Abby’s father was diagnosed with bilateral retinoblastoma in Kenya in 1946. Abby was also born with cancer in both eyes. She has an artificial eye and limited vision in her left eye that is now failing due to late effects of radiotherapy in infancy.
Abby studied geography at university, with emphasis on development in sub-Saharan Africa. She co-founded WE C Hope with Brenda Gallie, responding to the needs of one child and the desire to help many in developing countries. After receiving many requests for help from American families and adult survivors, she co-founded the US chapter to bring hope and encourage action across the country.
Abby enjoys listening to audio books, creative writing, open water swimming and long country walks.